The rupture of the fibrous cap is the critical event leading to thromboembolic complications on the luminal surface of advanced atherosclerotic plaques. The factors that set the stage for plaque disruption include progressive cap atrophy with loss of cells and matrix. Unfortunately, these beliefs are hard to test because of a lack of animal models. We propose to solve this problem by an interdisciplinary approach combining human tissue and animal model studies of molecular pathways that could underlie this process. In this project, we will study, using high-resolution magnetic resonance imaging, a cohort of patients with moderate internal carotid artery stenosis. We will test the hypothesis that the fibrous caps of these lesions generally are thick and that thinning of the cap develops after the plaque enlarges and the lumen narrows. We will also determine whether ischemic neurological events or plaque rupture assessed by histological evaluation of excised plaques correlates with fibrous cap thinning.